The season featured 13 actors credited in a starring capacity. All of the characters credited in the fifth season with the exception of Brooke Smith and T.R. Knight, who both departed during the previous season, continue to be credited as main cast members. Katherine Heigl departs the series temporarily in the fifth episode of the season and returns on two occasions (New History and I Like You So Much Better When You're Naked) until her subsequent permanent departure in the latter episode. She continues to be credited until the nineteenth episode of the season after which she is removed from the credits.

Season five guest star Jessica Capshaw returns on a regular basis and joins the main cast, while Kim Raver's status is also elevated during the season. Joining the series in the ninth episode as a recurring capacity, she appears in this fashion until she is promoted to the main cast for the seasons final six episodes, effective as of Sympathy For The Parents.

The season featured a wide array of guest cast members appearing in single episodes and multi-episode arcs. Kim Raver initially appeared as a guest star portraying Teddy but was elevated to a series regular mid-way through the series. In the wake of the merger with Mercy West, four recurring residents were added in the form of Jesse Williams' Jackson Avery, Sarah Drew'sApril Kepner, Robert Baker's Charles Percy and Nora Zehetner's Reed Adamson. Baker and Zehetner would depart the show during the season finale while Williams and Drew would become regular cast members for the following season. In addition Jason George joined the cast as Ben Warren, an anesthesiologist who would serve as a love interest for Bailey in the latter half of the season and Levin Rambin acted as Sloan Riley, the illegitimate, pregnant daughter of Mark Sloan.

The season also featured an appearance by former main cast member Kate Walsh appearing as her character Addison Montgomery, as part of the January 2010 Grey's Anatomy/Private Practice cross-over. Walsh was the only character from Private Practice to cross over to Grey's Anatomy and received a 'Special Guest Star' credit.

In addition, many household names joined the cast for one-episode arcs as patients including Martha Pimpton, Sara Gilbert, Marion Ross and Demi Lovato.

Episode number: 01
Original air date: September 24, 2009
Plot: The hospital staff is left to deal with the aftermath of George's passing. Hitting the staff hard, they all find unique ways to get through the various stages of grief as Izzie recuperates from her near-death experience. Callie and Izzie are forced to decide what to do with George's organs while Meredith and the rest of the staff try to continue living. the Cheif must deal with a devestating blow to his career while Derek considers a job offer.
Recurring characters:Debra Monk as Louise O'Malley
and Mitch Pileggi as Larry Jennings

Episode number: 02
Original air date: September 24, 2009
Plot: Everyone is struggling after losing one of their own and are turning to any distraction they can find. Meredith and Derek begin to enjoy the beginnings of their newly married life while Cristina and Owen are instructed to abstain from sex by Dr. Wyatt. Izzie continues to mourn her best friend and doesn't understand when starts Alex pulling away from her emotionally and Lexie considers the next step in her relationship with Mark. Meanwhile, Callie begins her new job as an attending at Mercy West.
Recurring characters:Amy Madigan as Katherine Wyatt
and Mitch Pileggi as Larry Jennings

Episode number: 03
Original air date: October 1, 2009
Plot: Several weeks after her near-death experience, a recovering Izzie returns to work and the other doctors start to question her ability. Meanwhile, nervous that there will be layoffs in the hospital in the wake of an announcement from the Chief, the Seattle Grace residents compete to survive the cuts, including Cristina who attempts to work alongside Arizona in pediatrics. Bailey and Alex's patient's already complex case is further complicated by her schizophrenic son and Callie faces her future in the wake of the announcement of the merger.
Recurring characters:Sarah Utterback as Olivia Harper

Episode number: 04
Original air date: October 8, 2009
Plot: When Meredith and Lexie's father Thatcher returns to the hospital with a failed liver Meredith is unsure of how to feel but, when Lexie isn't a match for a liver transplant, Meredith faces a crisis when Lexie begs her to come forward and save their father. Izzie emphasizes with a patient riddled with tumours while Alex grows tired of his current living situation. Mark, annoyed with Cristina's competitive zeal, tricks her into assisting on an unusual surgery and Arizona urges Callie to beg the Cheif for her job back.
Recurring characters:Jeff Perry as Thatcher Grey

Episode number: 07
Original air date: October 29, 2009
Plot: When a lab technician from the hospital has an inoperable tumor wrapped around his spine, he asks Derek to do the impossible- save his life and Derek juggles trying to perform a miracle and questioning Richard's authority by procceding with the risky procedure. Alex continues to be tested emotionally when he waits for Izzie to return for her treatment.
Recurring characters:Jesse Williams as Jackson Avery and Nora Zehetner as Reed Adamson

Episode number: 12
Original air date: January 21, 2010
Plot: After learning of Richard's drinking problem, Derek and Meredith come into conflict when Derek reveals his intentions to report Richard to the board and Meredith tries to protect her friend, but both are motivated by the desire to further their own career while Richard's drinking continues to affect his work. tensions run high between Teddy, Cristina and Owen in the aftermath of Teddy and Cristina's startling confrontation while Izzie returns home hoping to reconsile with Alex. Mark and Lexie hide indiscretions from eachother.
Recurring characters:Kim Raver as Teddy Altman, Mitch Pileggi as Larry Jennings and Jesse Williams as Jackson Avery

Episode number: 13
Original air date: February 04, 2010
Plot: As Derek begins his role as interim chief, the hospital faces a crisis when Bailey and Meredith's patient awakens from anesthesia mid-surgery and Derek faces a potential lawsui while trying to regain the trust of his coworkers and attempting to help Richard get back on track. Meanwhile, Teddy refuses to place Cristina on her service bringing about problems in Cristina and Owen's relationship while Arizona tests Alex out in Pediatrics. Mark refuses to speak to a heartbroken Lexie.

Episode number: 14
Original air date: February 11, 2010
Plot: The doctors treat dozens of patients after a roof collapses at a popular romantic restaraunt on Valentine's Day and they have to deal with the fallout. Derek and Meredith face their lives after reinventing themselves, Derek as the Cheif and Meredith as a married woman. Mark and Callie team up to persuade Sloan to do the right things for her baby while Lexie makes a drastic change in her bid to put Mark behind her. Callie and Arizona push Bailey into persuing a new love interest.

Episode number: 15
Original air date: February 10, 2010
Plot: In his new role as Chief, Derek restores the hospital lecture series and Richard, Bailey and Callie present to the group pivotal surgical cases from their pasts. Bailey reflects on her first days as a shy resident where she was forced to toughen up to make it as a surgeon, Callie nervous looks back on a polio case she and Alex had during his internship and Richard recalls a case in which he and Ellis worked on a patient diagnosed with GRID, a virus later called AIDS, and sheds light on the beginnings of their affair.

Episode number: 16
Original air date: March 4, 2010
Plot: When the famous doctor Harper Avery is rushed to Seattle Grace-Mercy West, the staff is stunned to learn that one of their own is related to the surgical legend when they all learn that Jackson is his grandson. Meredith and Jackson bond over their similiar surgical lineage while Harper's unorthodox request for his surgery causes tensions between Derek and his newest attending, Richard. Callie and Arizona try to push Mark and Teddy to move on from their rocky past relationships.

Episode number: 17
Original air date: March 11, 2010
Plot: In the wake of Harper Avery's visit, Richard and Owen compete for the opportunity to tackle an extremely difficult surgery when a patient with a complex tumor comes to Seattle Grace but the decision lies in the hands of Derek, who deems that Owen should take on the surgery, leaving Richard bitter. Bailey deals with her own personal struggles and consults Callie for help as she prepares for another date with Ben while Mark asks Teddy out on a date.

Episode number: 18
Original air date: March 25, 2010
Plot: When Teddy's patient seeks to end treatment and end her life she turns to Owen for help, but the situation triggers Owen's memories of his life at war and his past relationship with Teddy. Callie and Arizona have a difference of opinion regarding what their future holds after while Richard tries to adjust to his new role as an attending surgeron. Meredith becomes angry at Derek when he steals one of her surgeries.

Episode number: 19
Original air date: April 1, 2010
Plot: When Alex's younger brother arrives in Seattle with a hernia he is admitted to the hospital and the tenacious relationship between the brothers grows tense when Aaron discloses secrets about Alex that he kept well hidden to his fellow friends and doctors. Callie and Arizona both try to avoid talking about their differing opinions on their future while Derek catches Meredith of guard when he starts talking about having children. A devastating turn of events with a patient challenges Richard, Derek and Lexie as doctors.

Episode number: 20
Original air date: April 29, 2010
Plot: After Sloan returns to Mark's apartment just as she's going into labor Teddy, Cristina, Owen and a slill-fighting Callie and Arizona are on hand to help with the delivery. Mark then struggles with his grandson's pending adoption and tries to convince Sloan to raise the baby with him. Meanwhile Teddy sees Derek's invitation to illustrious cardiothoracic surgeon Tom Evans as a threat to her future employment at the hospital and Lexie is forced to become more assertive with Alex.

Episode number: 21
Original air date: May 6, 2010
Plot:Bailey preps the team with mandatory sensitivity training prior to admitting a 700-pound patient with compounded medical issues, and the case proves to be challenging in every sense of the word while Derek has to come face to face with a former patient’s husband in a wrongful death deposition. Spending time with a heart patient’s daughter forces Cristina to revisit her father's death while Meredith grows suspicious of Owen and Teddy's relationship. Callie and Arizona determine the future of their relationship and Alex receives divorce papers from Izzie.

Episode number: 22
Original air date: May 13, 2010
Plot: An elderly patient admitted into the E.R. for a heart condition sees a familiar face, a long lost love who happens to be in the E.R. as well for a fractured arm, and the staff find themselves caught up in their love story. Meredith makes a discovery which makes ehr question Owen's feelings for Cristina and Teddy and she confesses her suspicions which inevitably messes with Cristina's head. Alex treats a troubled teenage patient whose parents believe she has schizophrenia while Lexie finds herself conflicted about her feelings for Alex and Mark when one of Mark's trysts becomes public knowledge.

Episode number: 23
Original air date: May 20, 2010
Plot: Seattle Grace is hit with a crisis like no other in it's history which leaves the lives of the docors hanging in the balance while a shooter roams the halls, gunning for Derek who he holds responsible for the death of his wife. Amidst the crisis, Meredith discovers life-changing news at an inopertune time and Cristina makes a choice about her relationship with Owen after they reach a crossroads. Mark and Lexie are forced to work together in a difficult situation while the lockdown forces Callie and Arizona's issues.

Episode number: 24
Original air date: May 10, 2010
Plot: The deadly situation at Seattle Grace hits closer to home when Derek is shot and Cristina's surgical skills are put to the ultimate test his life is in her hand while Meredith struggles with the Derek's life hanging in the balance. Lexie makes a devestating realization about her current circumstances as she and Mark work to save Alex while Bailey desperatly strives to save the life of a fellow doctor.